The nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor alpha: Genetic evidence from patients with mutations of the thyroid hormone receptor alpha gene (THRA) indicates that the dominant negative activity of mutants underlies the pathological manifestations. However, the molecular mechanisms by which TRalpha1 mutants exert dominant negative activity in vivo are not clear. We tested the hypothesis that the severe hypothyroidism in patients with THRA mutations is due to an inability of TRalpha1mutants to properly release the nuclear corepressors (NCORs), thereby T3-mediated transcription activity. We crossed TRalpha1PV/+ mice, expressing a dominant negative TRalpha1 mutant (TRalpha1PV), with mice expressing a mutant Ncor1 allele (Ncor1deltaID mice) that cannot recruit the TR or PV mutant. TRalpha1PV shares the same C-terminal mutated sequences as those of patients with frameshift mutations of the THRA gene. Remarkably, NCOR1deltaID ameliorated abnormalities in the thyroid-pituitary axis of TRalpha1PV/+ mice. The severe retarded growth, infertility, and delayed bone development were partially reverted in TRalpha1PV/+ mice expressing NCOR1deltaID. The impaired adipogenesis was partially corrected by de-repression of peroxisome-proliferator activated receptor gamma and CCAAT/enhancer-binding protein alpha gene, due to inability of TRalpha1PV to recruit NCOR1deltaID to form repressor complex. Thus, the aberrant recruitment of NCOR1 by TRalpha1 mutants could lead to clinical hypothyroidism in humans. Therefore, therapies aimed at the TRalpha1-NCOR1 interaction or its downstream actions could be tested as potential targets in treating TRalpha1 mutant-mediated hypothyroidism in patients.